He Siyu, Bai June, Zhang Lixin, Yuan Hao, Ma Cui, Wang Xiaoying, Guan Xiaoyu, Mei Jian, Zhu Xiangrui, Xin Wei, Zhu Daling
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China.
College of Pharmacy, Harbin Medical University, Harbin 150081, P.R. China.
iScience. 2024 Sep 12;27(10):110900. doi: 10.1016/j.isci.2024.110900. eCollection 2024 Oct 18.
The abnormal expression of circular RNAs (circRNAs) is emerging as a critical cause in regulation of pathological changes of hypoxic pulmonary hypertension (PH), in which ferroptosis is a new pathological change reported recently. However, how circRNAs regulate ferroptosis remains unclear. Here, we proved a significant decrease in circMyst4 expression in hypoxia. assays revealed that circMyst4 alleviated hypoxic pulmonary artery smooth muscle cell (PASMC) ferroptosis through directly combing with DDX5 in the nucleus to promote GPX4 mRNA processing and inhibiting the formation of the Eef1a1/ACSL4 complex in the cytoplasm. Additionally, superenhancer (SE) was verified to drive the generation of circMyst4. assays revealed that circMyst4 inhibited the progression of hypoxic PH. Overall, SE-driven circMyst4 may be a new potential therapeutic target for mediating PASMC ferroptosis through promoting DDX5-regulated GPX4 mRNA processing and inhibiting the binding between Eef1a1 and ACSL4.
环状RNA（circRNAs）的异常表达正逐渐成为低氧性肺动脉高压（PH）病理变化调控中的一个关键原因，其中铁死亡是最近报道的一种新的病理变化。然而，circRNAs如何调节铁死亡仍不清楚。在此，我们证实缺氧条件下circMyst4的表达显著降低。实验表明，circMyst4通过在细胞核中直接与DDX5结合，促进GPX4 mRNA加工，并在细胞质中抑制Eef1a1/ACSL4复合物的形成，从而减轻低氧性肺动脉平滑肌细胞（PASMC）的铁死亡。此外，超增强子（SE）被证实可驱动circMyst4的产生。实验表明，circMyst4可抑制低氧性PH的进展。总体而言，SE驱动的circMyst4可能是一个新的潜在治疗靶点，通过促进DDX5调节的GPX4 mRNA加工和抑制Eef1a1与ACSL4之间的结合来介导PASMC铁死亡。
